Abstract 478: Engineering viruses for the next generation targeted cancer therapy

Abstract The development of targeted therapies, including monoclonal antibodies, CAR-T cells, nanobodies, and combination treatments, has significantly advanced cancer management, particularly for HER2-positive tumors. Despite these advancements, challenges such as instability, high toxicity, immune responses, rapid clearance, drug resistance, and exorbitant manufacturing costs persist. A major contributor to these costs is the reliance on mammalian cell systems for production. Additionally, minimizing off-target effects remains a critical concern for targeted therapies.In this study, we engineered virus-like particles (VLPs) to selectively target HER2-positive tumors with minimal off-target effects. These VLPs were further designed to carry genetically expressed RNA interference (RNAi) systems for in situ gene silencing. Cryo-electron microscopy (Cryo-EM) was employed to characterize the functionalization of the VLP exterior and verify the packaging of the RNAi cargo. This novel single-cell approach combines targeted tumor homing with siRNA delivery, enabling simultaneous tumor targeting and silencing of the PDL1 gene. The multivalent nature of VLPs allows for the incorporation of multiple peptides, enhancing tumor affinity and specificity. With a size of approximately 35 nm, VLPs exhibit favorable pharmacokinetics, including reduced clearance and effective tumor homing. A key advantage of our approach is the ability to express VLPs in Escherichia coli systems, significantly reducing production costs compared to traditional mammalian cell-based systems, making the therapy more accessible.Our findings demonstrate that intravenously administered HER2-targeting VLPs achieve high specificity and affinity for HER2-positive tumors. Once localized, the VLPs penetrate deeply into tumor tissue, delivering RNAi cargo to silence PDL1 expression. Light sheet microscopy will be used to visualize tumor architecture in three dimensions to further investigate tumor penetration, offering a more comprehensive view than traditional cryosections. By inhibiting tumor growth and recruiting immune cells, this approach offers a dual mechanism of action: direct tumor suppression and enhanced immune-mediated clearance. Furthermore, VLPs provide unique advantages such as efficient cell penetration, scalable production, and robust cargo delivery, positioning them as a promising platform for cost-effective and effective cancer therapies. Citation Format: Ikeda Trashi, Jeremiah Gassensmith. Engineering viruses for the next generation targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 478.